RNA interference offers the potential of a novel therapeutic approach for treating skin disorders. The technology to design, screen and identify potent, selective, and stable small interfering RNAs (siRNAs) is now relatively straightforward. The ability to deliver [unreadable] these potential therapeutics to appropriate skin cells has not kept pace. The long-term goal of this project is to develop a mechanism to efficiently and effectively deliver siRNAs to appropriate skin cells in a way that can be readily translated to use in humans. In Phase I, we investigate a number of mouse skin reporter systems for their suitability to monitor siRNA delivery to keratinocytes. Several of these models use reporter genes that can be non-invasively detected at multiple timepoints using in vivo [unreadable] whole-animal imaging, while others rely on real-time PCR quantitation of endogenous gene targets. A human skin equivalent, with or without mutant keratin genes resulting in disease phenotype, is also analyzed as a model for delivery of functional siRNA to keratinocytes. In addition, the stability, half-lives, and distribution of siRNAs will be determined in both human and mouse skin. The proposed aims in Phase 1 are quite straightforward; however, these reporter systems are crucial for laying the groundwork for demonstrating effective delivery of functional siRNAs. In Phase 2, innovative skin [unreadable] delivery technologies for selected siRNAs are screened and optimized in the most appropriate systems identified in Phase 1, and animal toxicology and pharmacokinetic experiments are performed in preparation for clinical trials. [unreadable] [unreadable] [unreadable]